Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness

Abstract

Aims/hypothesis Targeted metabolomic and transcriptomic approaches were used to evaluate the relationship between skeletal muscle metabolite signatures, gene expression profiles and clinical outcomes in response to various exercise training interventions. We hypothesised that changes in mitochondrial metabolic intermediates would predict improvements in clinical risk factors, thereby offering novel insights into potential mechanisms. Methods Subjects at risk of metabolic disease were randomised to six months of inactivity or one of five aerobic and/or resistance training programmes (n = 112). Pre/post-intervention assessments included cardiorespiratory fitness (V̇O2peak), serum triacylglycerols (TGs) and insulin sensitivity (SI). In this secondary analysis, muscle biopsy specimens were used for targeted mass spectrometry-based analysis of metabolic intermediates and measurement of mRNA expression of genes involved in metabolism. Results Exercise regimens with the largest energy expenditure produced robust increases in muscle concentrations of even-chain acylcarnitines (median 37–488%), which correlated positively with increased expression of genes involved in muscle uptake and oxidation of fatty acids. Along with free carnitine, the aforementioned acylcarnitine metabolites were related to improvements in V̇O2peak, TGs and SI (R = 0.20–0.31, p < 0.05). Muscle concentrations of the tricarboxylic acid cycle intermediates succinate and succinylcarnitine (R = 0.39 and 0.24, p < 0.05) emerged as the strongest correlates of SI. Conclusions/interpretation The metabolic signatures of exercise-trained skeletal muscle reflected reprogramming of mitochondrial function and intermediary metabolism and correlated with changes in cardiometabolic fitness. Succinate metabolism and the succinate dehydrogenase complex emerged as a potential regulatory node that intersects with whole-body insulin sensitivity. This study identifies new avenues for mechanistic research aimed at understanding the health benefits of physical activity. Trial registration ClinicalTrials.gov NCT00200993 and NCT00275145

Long term (3 years) weight loss after low intensity endurance training targeted at the level of maximal muscular lipid oxidation

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Changes in Gene Expression in Responders and Nonresponders to a Low-Intensity Walking Intervention

“…This discovery of interindividual response to low-intensity exercise prompted us to further examine skeletal muscle gene expression after stratification of the IGT cohort based on the normalization of blood glucose levels during an OGTT after the exercise intervention. Although the effects of various exercise training regimens on gene expression profiles in skeletal muscle have been assessed (19,(23)(24)(25)(26)(27)(28), comparatively limited information is available on the adaptive response to exercise training in people at risk for developing type 2 diabetes (29). We have taken a focused approach to gain insight into the molecular "fingerprint" associated with the early indications of IGT and the adaptive response to low-intensity unsupervised exercise.…”

Plasma Metabolite Profiles in Response to Chronic Exercise

“…Notably, this study focused on free fatty acids, acylcarnitines and a subset of amino acids. More recently, the same group employed a larger, targeted metabolomics platform in skeletal muscle biopsies in an expanded sample, and found that a high amount of vigorous intensity aerobic exercise significantly increased concentrations of even-, medium-, and long-chain acylcarnitines, while resistance training and a low-amount of vigorous intensity aerobic exercise preferentially increased short- and medium-chain acylcarnitines (17). …”